Evaluation of NAD(+)-dependent DNA ligase of mycobacteria as a potential target for antibiotics

Mycobacteria contain genes for several DNA ligases, including ligA, which encodes a NAD+-dependent enzyme that has been postulated to be a target for novel antibacterial compounds. Using a homologous recombination system, direct evidence is presented that wild-type ligA cannot be deleted from the chromosome of Mycobacterium smegmatis. Deletions of native ligA in M. smegmatis could be obtained only after the integration of an extra copy of M. smegmatis or Mycobacterium tuberculosis ligA into the attB site of the chromosome, with expression controlled by chemically inducible promoters. The four ATP-dependent DNA ligases encoded by the M. smegmatis chromosome were unable to replace the function of LigA. Interestingly, the LigA protein from M. smegmatis could be substituted with the NAD+-dependent DNA ligase of Escherichia coli or the ATP-dependent ligase of bacteriophage T4. The conditional mutant strains allowed the analysis of the effect of LigA depletion on the growth of M. smegmatis. The protein level of the conditional mutants was estimated by Western blot analysis using antibodies raised against LigA of M. tuberculosis. This revealed that a strong overproduction or depletion of LigA did not affect the growth or survival of mycobacteria under standard laboratory conditions. In conclusion, although NAD+-dependent DNA ligase is essential for mycobacterial viability, only low levels of protein are required for growth. These findings suggest that very efficient inhibition of enzyme activity would be required if NAD+-dependent DNA ligase is to be useful as an antibiotic target in mycobacteria. The strains developed here will provide useful tools for the evaluation of the efficacy of any appropriate compounds in mycobacteria

Neighborly boxes and bipartite coverings; constructions and conjectures

Two axis-aligned boxes in $\mathbb{R}^d$ are \emph{$k$-neighborly} if their intersection has dimension at least $d-k$ and at most $d-1$. The maximum number of pairwise $k$-neighborly boxes in $\mathbb{R}^d$ is denoted by $n(k,d)$. It is known that $n(k,d)=\Theta(d^k)$, for fixed $1\leqslant k\leqslant d$, but exact formulas are known only in three cases: $k=1$, $k=d-1$, and $k=d$. In particular, the formula $n(1,d)=d+1$ is equivalent to the famous theorem of Graham and Pollak on bipartite partitions of cliques. In this paper we are dealing with the case $k=2$. We give a new construction of $k$-neighborly \emph{codes} giving better lower bounds on $n(2,d)$. The construction is recursive in nature and uses a kind of ``algebra'' on \emph{lists} of ternary strings, which encode neighborly boxes in a familiar way. Moreover, we conjecture that our construction is optimal and gives an explicit formula for $n(2,d)$. This supposition is supported by some numerical experiments and some partial results on related open problems which are recalled

A new upper bound on the number of neighborly boxes in R^d

A new upper bound on the number of neighborly boxes in R^d is given. We apply a classical result of Kleitman on the maximum size of sets with a given diameter in discrete hypercubes. We also present results of some computational experiments and an emerging conjecture

Search for universality in one-dimensional ballistic annihilation kinetics

We study the kinetics of ballistic annihilation for a one-dimensional ideal gas with continuous velocity distribution. A dynamical scaling theory for the long time behavior of the system is derived. Its validity is supported by extensive numerical simulations for several velocity distributions. This leads us to the conjecture that all the continuous velocity distributions \phi(v) which are symmetric, regular and such that \phi(0) does not vanish, are attracted in the long time regime towards the same Gaussian distribution and thus belong to the same universality class. Moreover, it is found that the particle density decays as n(t)~t^{-\alpha}, with \alpha=0.785 +/- 0.005.Comment: 8 pages, needs multicol, epsf and revtex. 8 postscript figures included. Submitted to Phys. Rev. E. Also avaiable at http://mykonos.unige.ch/~rey/publi.html#Secon

Clinical implications of GWAS variants associated with differentiated thyroid cancer

The genetic risk of differentiated thyroid cancer (DTC) probably consists of multiple low-penetrance, single-nucleotide polymorphisms (SNP). Such markers are difficult to uncover by linkage analysis but can be revealed by association studies. Genome-wide association studies (GWASs) have uncovered 31 SNPs associated with DTC. These markers carry a low to moderate risk for DTC, but their cumulative effect increases with each successive risk allele. These data support the important contribution of low penetrance variants in the pathogenesis of DTC. Contrary to somatic mutations such as BRAFV600E, germline variants can be ascertained prior to surgical treatment. Therefore, we hypothesise that GWAS SNPs might impact the clinical course of DTC and we can benefit from this knowledge in choosing a treatment strategy. Several associations between clinical factors and GWAS markers have been reported so far. The most important are associations between rs966423 and mortality (HR = 1.60, p = 0.038), extrathyroidal extension (ETE) (OR = 1.57, p = 0.019); rs965513 and tumour diameter (slope of regression 0.14, p = 0.025), lymph node metastasis (OR = 1.59, p = 0.030) and ETE (OR = 1.29, p = 0.045); rs944289 and distant metastasis (OR = 0.58, p = 0.042); and rs116909374 and lymph node metastasis (OR = 0.61, p = 0.016). These findings show that GWAS SNPs are not only the ignition factors (together with environmental factors) for malignant transformation of thyrocytes but might also impact the clinical course of DTC. Surprisingly, it is not always the risk allele for DTC that is associated with worse clinical outcome. The second interesting observation is that GWAS SNPs show different associations with DTC clinical features depending on their histological subtypes. These point to the complexity of DTC with putatively different roles of genes at different stages of DTC development. (Endokrynol Pol 2019; 70 (5): 423–429

Kinetics of ballistic annihilation and branching

We consider a one-dimensional model consisting of an assembly of two-velocity particles moving freely between collisions. When two particles meet, they instantaneously annihilate each other and disappear from the system. Moreover each moving particle can spontaneously generate an offspring having the same velocity as its mother with probability 1-q. This model is solved analytically in mean-field approximation and studied by numerical simulations. It is found that for q=1/2 the system exhibits a dynamical phase transition. For q<1/2, the slow dynamics of the system is governed by the coarsening of clusters of particles having the same velocities, while for q>1/2 the system relaxes rapidly towards its stationary state characterized by a distribution of small cluster sizes.Comment: 10 pages, 11 figures, uses multicol, epic, eepic and eepicemu. Also avaiable at http://mykonos.unige.ch/~rey/pubt.htm

Safety and feasibility of Lin- cells administration to ALS patients : a novel view on humoral factors and miRNA profiles

Therapeutic options for amyotrophic lateral sclerosis (ALS) are still limited. Great hopes, however, are placed in growth factors that show neuroprotective abilities (e.g., nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF)) and in the immune modulating features, in particular, the anti-inflammatory effects. In our study we aimed to investigate whether a bone marrow-derived lineage-negative (Lin-) cells population, after autologous application into cerebrospinal fluid (CSF), is able to produce noticeable concentrations of trophic factors and inflammatory-related proteins and thus influence the clinical course of ALS. To our knowledge, the evaluation of Lin- cells transplantation for ALS treatment has not been previously reported. Early hematopoietic Lin- cells were isolated from twelve ALS patients&rsquo; bone marrow, and later, the suspension of cells was administered into the subarachnoid space by lumbar puncture. Concentrations of selected proteins in the CSF and plasma were quantified by multiplex fluorescent bead-based immunoassays at different timepoints post-transplantation. We also chose microRNAs (miRNAs) related to muscle biology (miRNA-1, miRNA-133a, and miRNA-206) and angiogenesis and inflammation (miRNA-155 and miRNA-378) and tested, for the first time, their expression profiles in the CSF and plasma of ALS patients after Lin- cells transplantation. The injection of bone marrow cells resulted in decreased concentration of selected inflammatory proteins (C3) after Lin- cells injection, particularly in patients who had a better clinical outcome. Moreover, several analyzed miRNAs have changed expression levels in the CSF and plasma of ALS patients subsequent to Lin- cells administration. Interestingly, the expression of miR-206 increased in ALS patients, while miR-378 decreased both in the CSF and plasma one month after the cells&rsquo; injection. We propose that autologous lineage-negative early hematopoietic cells injected intrathecally may be a safe and feasible source of material for transplantations to the central nervous system (CNS) environment aimed at anti-inflammatory support provision for ALS adjuvant treatment strategies. Further research is needed to evaluate whether the observed effects could significantly influence the ALS progression

Interatomic potentials of van der Waals dimers Hg2Hg_{2} and Cd2Cd_{2} : probing discrepancies between theory and experiment

Results of new all-electron ab initio calculations and revisit of experimental studies of the interatomic potentials of lower-lying ungerade excited and ground electronic energy states of the Hg_{2} and Cd_{2} van der Waals complexes are used as probes of discrepancies between theory and experiment. From simulations of the previously and presently measured LIF excitation and dispersed emission spectra new analytical representations of the excited- and the ground-state interatomic potentials are proposed. An inverted perturbation approach was also used to improve the studied interatomic potentials. The comparison of the new ab-initio calculated potentials with the results of the analyses illustrates an improve theory-to-experiment agreement for such a demanding system like Hg_{2} or Cd_{2}

Interpreting myocardial perfusion scintigraphy using single-photon emission computed tomography. Part 1

This article discusses the protocol for myocardial perfusion scintigraphy performed with single-photon emission computed tomography (SPECT). Indications for SPECT are listed with consideration given to the results of the increasingly more common angio-CT examinations of the coronary arteries (multislice computed tomography). The paper also presents basic information about interpreting the results, including the scores of left ventricle myocardial perfusion using the 17-segment polar map, and explains the concept of total perfusion deficit